Вы находитесь на странице: 1из 9

The BrainHeart Connection

Martin A. Samuels
Circulation. 2007;116:77-84
doi: 10.1161/CIRCULATIONAHA.106.678995
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2007 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/116/1/77

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/

Downloaded from http://circ.ahajournals.org/ by guest on September 1, 2014

Contemporary Reviews in Cardiovascular Medicine


The BrainHeart Connection
Martin A. Samuels, MD

eurocardiology has many dimensions, but it may be


conceptualized as divided into 3 major categories: the
hearts effects on the brain (eg, cardiac source embolic
stroke), the brains effects on the heart (eg, neurogenic heart
disease), and neurocardiac syndromes (eg, Friedreich disease). The present review deals with the nervous systems
capacity to injure the heart. This subject is inherently important but also represents an example of a much more widespread and conceptually fascinating area of neurovisceral
damage in general.

History of Learning the Nature of the


BrainHeart Connection
In 1942, at the culmination of his distinguished career as
Professor of Physiology at Harvard Medical School, Walter
B. Cannon published a remarkable paper entitled Voodoo
Death,1 in which he recounted anecdotal experiences,
largely from the anthropology literature, of death from fright.
These often remote events, drawn from widely disparate parts
of the world, had several features in common. They were all
induced by an absolute belief that an external force, such as
a wizard or medicine man, could, at will, cause demise and
that the victim himself had no power to alter this course. This
perceived lack of control over a powerful external force is the
sine qua non for all the cases recounted by Cannon, who
postulated that death was caused by a lasting and intense
action of the sympathico-adrenal system. Cannon believed
that this phenomenon was limited to societies in which the
people were so superstitious, so ignorant, that they feel
themselves bewildered strangers in a hostile world. Instead of
knowledge, they have fertile and unrestricted imaginations
which fill their environment with all manner of evil spirits
capable of affecting their lives disastrously. Over the years
since Cannons observations, evidence has accumulated to
support his concept that voodoo death is, in fact, a real
phenomenon but, far from being limited to ancient peoples,
may be a basic biological principle that provides an important
clue to understanding the phenomenon of sudden death in
modern society as well as providing a window into the world
of neurovisceral disease (also known as psychosomatic
illness).
George Engel collected 160 accounts from the lay press of
sudden death that were attributed to disruptive life events.2
He found that such events could be divided into 8 categories:

(1) the impact of the collapse or death of a close person; (2)


during acute grief; (3) on threat of loss of a close person; (4)
during mourning or on an anniversary; (5) on loss of status or
self-esteem; (6) personal danger or threat of injury; (7) after
danger is over; (8) reunion, triumph, or happy ending.
Common to all is that they involve events impossible for the
victim to ignore and to which the response is overwhelming
excitation, giving up, or both.
In 1957, Curt Richter reported on a series of experiments
aimed to elucidate the mechanism of Cannons voodoo
death.3 Richter, a former student of Cannon, pursued an
incidental discovery of an epidemic of sudden death in a
colony of rodents, which was induced when a colleague,
Gordon Kennedy, had clipped the whiskers of the animals to
prevent contamination of the urine collection. Richter studied
the length of time that domesticated rats could swim at
various water temperatures and found that at a water temperature of 93C these rats could swim for 60 to 80 minutes.
However, if the animals whiskers were trimmed, it would
invariably drown within a few minutes. When carrying out
similar experiments with fierce wild rats, he noted that a
number of factors contributed to the tendency for sudden
death, the most important of which was restraint, which
involved holding the animals and confinement in a glass
swimming jar with no chance of escape. By trimming the
rats whiskers, a procedure that destroys possibly their most
important proprioceptive mechanism, the tendency for early
demise was exacerbated. In the case of the calm domesticated
animals in which restraint and confinement were apparently
not significant stressors, removal of whiskers rendered these
animals as fearful as wild rats with a corresponding tendency
for sudden death. ECGs taken during the process showed
development of a bradycardia prior to death, and adrenalectomy did not protect the animals. Furthermore, atropine
protected some of the animals, and cholinergic drugs led to an
even more rapid demise. All this was taken as evidence that
overactivity of the sympathetic nervous system was not the
cause of the death but rather it was caused by increased vagal
tone.
We now believe that the apparently opposite conclusions
of Cannon and Richter are not mutually exclusive, but rather
that a generalized autonomic storm, which occurs as a result
of a life-threatening stressor, will have both sympathetic and
parasympathetic effects. The apparent predominance of one

From the Department of Neurology, Brigham and Womens Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Dr Martin A. Samuels, Department of Neurology, Brigham and Womens Hospital, Harvard Medical School, 75 Francis St, Boston,
MA 02115. E-mail msamuels@partners.org
(Circulation. 2007;116:77-84.)
2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

DOI: 10.1161/CIRCULATIONAHA.106.678995

77
Downloaded from http://circ.ahajournals.org/
by guest on September 1, 2014

78

Circulation

July 3, 2007

over the other depends on the parameter measured (eg, heart


rate, blood pressure) and the timing of the observations in
relation to the stressor (eg, early events tend to be dominated
by sympathetic effects, whereas late events tend to be
dominated by parasympathetic effects). Cerebral hemispheral
dominance with regard to autonomic control (right predominantly sympathetic and left predominantly parasympathetic)
probably also contributes to the dominant mechanism of
sudden death (ie, sympathetic versus vagal) in a given
person.4
In human beings, one of the easily accessible windows into
autonomic activity is the ECG. Edwin Byer and colleagues
reported 6 patients whose ECGs showed large upright T
waves and long QT intervals.5 Two of these patients had
hypertensive encephalopathy, 1 patient had a brain stem
stroke with neurogenic pulmonary edema, 1 patient had an
intracerebral hemorrhage, 1 patient had a postpartum ischemic stroke possibly related to toxemia of pregnancy, and 1
patient had no medical history except a blood pressure of
210/110 mm Hg. On the basis of experimental results of
cooling or warming the endocardial surface of a dogs left
ventricle, Byer and colleagues concluded that these ECG
changes were caused by subendocardial ischemia. Harold
Levine reported on several disorders other than ischemic
heart disease that could produce ECG changes reminiscent of
coronary disease.6 Among these was a 69-year-old woman
who was admitted and remained in coma. Her admission
ECG showed deeply inverted T waves in the anterior and
lateral precordial leads. Two days later, it showed ST segment elevation with less deeply inverted T waves, a pattern
suggestive of myocardial infarction. However, at autopsy a
ruptured berry aneurysm was found and no evidence of
myocardial infarction or pericarditis was noted. Levine did
not propose a specific mechanism but referred to experimental work on the production of cardiac arrhythmias by basal
ganglia stimulation and ST and T-wave changes induced by
injection of caffeine into the cerebral ventricle.
George Burch and colleagues7 reported on 17 patients who
were said to have cerebrovascular accidents (ie, strokes). In
14 of the 17, hemorrhage was demonstrated by lumbar
puncture. It is not possible to determine which of these
patients had hemorrhagic infarction, intracerebral hemorrhage, and subarachnoid hemorrhage, and no data about the
territory of the strokes are available. The essential features of
the ECG abnormalities were: (1) long QT intervals in all
patients; (2) large, usually inverted, T waves in all patients;
and (3) U waves in 11 of the 17 patients.7
Cropp and Manning8 reported on the details of ECG
abnormalities in 29 patients with subarachnoid hemorrhage.
Twenty-two of these patients survived. Two of those who
died had no postmortem examination, which left 5 patients in
whom autopsies confirmed the presence of a ruptured cerebral aneurysm. In 3 of these 5 patients, the heart and coronary
arteries were said to be normal, but the details of the
pathological examination were not revealed. The point is
made that ECG changes seen in the context of neurological
disease do not represent ischemic heart disease but are merely
a manifestation of autonomic dysregulation, possibly caused
by a lesion that affected the cortical representation of the

autonomic nervous system. The authors argued that Brodmann area 13 on the orbital surface of the frontal lobe and
area 24 on the anterior cingulate gyrus were the cortical
centers for cardiovascular control.
There is clear evidence that cardiac lesions can be produced as the result of nervous system disease. The concept of
visceral organ dysfunction that occurs as a result of neurological stimuli can be traced to Ivan Pavlov. Hans Selye, a
student of Pavlov, described electrolytesteroid cardiopathy
with necroses (ESCN).9 Selyes view was that this cardiac
lesion was common and often described by different names in
the literature. He argued that this lesion was distinct from the
coagulation necrosis that occurred as a result of ischemic
disease, but that it could exist in the same heart. Selye
demonstrated that certain steroids and other hormones created
a predisposition for the development of ESCN, but that other
factors were required for ESCN to develop. The most
effective conditioning steroid was 2- -methyl-9- fluorocortisol. Among the factors that led to ESCN in
steroid-sensitized animals were certain electrolytes (eg,
NaH2PO4), various hormones (eg, vasopressin, adrenaline,
insulin, thyroxine), certain vitamins (eg, dihydrotachysterol),
cardiac glycosides, surgical interventions (eg, cardiac reperfusion after ischemia), and psychic or nervous stimuli (eg,
restraint, fright). The cardiac lesions could not be prevented
by adrenalectomy, which suggests that the process, if related
to sympathetic hyperactivity, must exert its influence by
direct neural connection to the heart rather than by a bloodborne route.
Cardiac lesions may be produced in rats by pretreatment
with either 2--methyl-9--fluorohydrocortisone (fluorocortisol), dihydrotachysterol (calciferol), or thyroxine and then
restraint of the animals on a board for 15 hours or with cold
stress.10 Agents that act by inhibition of the catecholaminemobilizing reflex arc at the hypothalamic level (eg, chlorpromazine) or by blockade of only the circulating but not the
neurogenic intramyocardial catecholamines (eg, dibenamine)
were the least effective for protection of cardiac muscle,
whereas those drugs that act by ganglionic blockade (eg,
mecamylamine) or by direct intramyocardial catecholaminedepletion (eg, reserpine) were the most effective. Furthermore, it is clear that blood catecholamine levels are often
normal but that identical ECG findings are seen with high
systemic catecholamines. These clinical and pharmacological
data support the concept that the cardiac necrosis is caused by
catecholamine toxicity and that catecholamines released directly into the heart via neural connections are much more
toxic than those that reach the heart via the bloodstream,
though clearly the 2 routes could be additive in the intact,
nonadrenalectomized animal. Intracoronary infusions of epinephrine reproduce the characteristic ECG pattern of neurocardiac disease, which is reminiscent of subendocardial
ischemia, though no ischemic lesion can be found in the
hearts of dogs euthanized after several months of infusions.11
In the years that followed, numerous reports emanated from
around the world that documented the production of cardiac
repolarization abnormalities in the context of various neurological catastrophes and that proposed that this was caused by
an autonomic storm. It seemed likely that the connection

Downloaded from http://circ.ahajournals.org/ by guest on September 1, 2014

Samuels
between neuropsychiatric illness and the visceral organs
would be provided by the autonomic nervous system.
Melville et al12 produced ECG changes and myocardial
necrosis by stimulation of the hypothalamus of cats. With
anterior hypothalamic stimulation, parasympathetic responses
occurred, predominantly in the form of bradycardia. Lateral
hypothalamic stimulation produced tachycardia and ST segment depressions. With intense bilateral and repeated lateral
stimulation, persistent irreversible ECG changes occurred and
postmortem examination revealed a stereotyped cardiac lesion characterized by intense cytoplasmic eosinophilia with
loss of cross-striations and some hemorrhage. The coronary
arteries were normal without occlusion. Although Melville
referred to this lesion as infarction, it is probably best to
reserve that term for coagulation necrosis caused by ischemia.
This lesion is probably identical to Selyes ESCN and would
now be called coagulative myocytolysis, myofibrillar degeneration, or contraction band necrosis. More recently, Oppenheimer and Cechetto have mapped the chronotropic organizational structure in the rat insular cortex, which
demonstrates that sympathetic innervation arises from a more
rostral part of the posterior insula then causes parasympathetic innervation.13 The insula and thalamus had already
been shown to have a sensory viscerotropic representation
that included the termination of cardiopulmonary afferents.14
The central role of the insula in the control of cardiovascular
function has been supported by a robust experimental and
clinical literature.15,16
Despite the fact that myocardial damage could definitely
be produced in animals, until the mid-1960s there was little
recognition that this actually occurred in human beings with
acute neurological or psychiatric illness until Koskelo and
colleagues17 reported on 3 patients with ECG changes caused
by subarachnoid hemorrhage who were noted on postmortem
examination to have several small subendocardial petechial
hemorrhages. Connor18 reported focal myocytolysis in 8% of
231 autopsies, with the highest incidence seen in patients who
suffered fatal intracranial hemorrhages. The lesion reported
by Connor conforms to the descriptions of Selyes ESCN or
what might now be called myofibrillar degeneration, coagulative myocytolysis, or contraction band necrosis. Connor
pointed out that previous pathology reports probably overlooked the lesion because of the fact that it was multifocal,
with each individual focus being quite small, which would
require extensive tissue sampling. It is clear now that even
Connor underestimated the prevalence of the lesion and that
serial sections are required to rigorously exclude its presence.
Greenshoot and Reichenbach19 reported on 3 new patients
with subarachnoid hemorrhage and a review of 6 previous
patients from the same medical center. All 9 of these patients
had cardiac lesions of varying degrees of severity that ranged
from eosinophilia with preservation of cross-striations to
transformation of the myocardial cell cytoplasm into dense
eosinophilic transverse bands with intervening granularity,
sometimes with endocardial hemorrhages. Both the ECG
abnormalities and the cardiac pathology could be reproduced
in cats given mesencephalic reticular formation stimulation.
Adrenalectomy did not protect the hearts, which supports the

The BrainHeart Connection

79

contention that the ECG changes and cardiac lesions are due
to direct intracardiac release of catecholamines.
Hawkins and Clower20 injected blood intracranially into
mice, which thereby produced the characteristic myocardial
lesions. The number of lesions could be reduced but not
obliterated by pretreatment with adrenalectomy and the use of
either atropine or reserpine, which suggested that the cause of
the lesions was in part caused by sympathetic overactivity
(humoral arrival at the myocardium from the adrenal and by
direct release into the muscle by intracardiac nerves) and in
part caused by parasympathetic overactivity. This supports
the concept that the cause is an autonomic storm with a
contribution from both divisions to the pathogenesis.
Jacob et al21 produced subarachnoid hemorrhage experimentally in dogs and carefully studied the sequential hemodynamic and ultrastructural changes that occurred. The hemodynamic changes occurred in 4 stages and directly
paralleled the effects seen with intravenous norepinephrine
injections. These stages were: (1) dramatic rise in systemic
blood pressure; (2) extreme sinus tachycardia with various
arrhythmias (eg, nodal or ventricular tachycardia, bradycardia, atrioventricular block, ventricular premature beats, ventricular tachycardia, ventricular fibrillation with sudden
death), all of which could be suppressed by bilateral vagotomy or orbital frontal resection; (3) rise in left ventricular
pressure parallel to rise in systemic pressure; and (4) up to
2-fold increase in coronary blood flow.
Ultrastructurally, a series of 3 stereotyped events occurred
that could be imitated exactly with norepinephrine injections.
These were: (1) migration of intramitochondrial granules that
contained Ca2 to the periphery of the mitochondria; (2)
disappearance of these granules; and (3) myofilament disintegration at the I bands while the density of the I band was
increased in the intact sarcomeres.21
Partially successful efforts to modify the developments of
neurocardiac lesions were made with reserpine pretreatment
in mice subjected to simulated intracranial hemorrhage22 and
by Hunt and Gore,23 who pretreated a group of rats with
propranolol and then attempted to produce cardiac lesions
with intracranial blood injections. No lesions were found in
the control animals, but they were found in 21 of the 46
untreated rats and in only 4 of the 22 treated rats. This
suggested that neurological influences via catecholamines
may be at least partly responsible for cardiac cell death. More
modern studies have confirmed the fact that myocardial
injury occurs in the context of subarachnoid hemorrhage and
that the likelihood of myocardial necrosis was correlated with
the severity of the clinical neurological state as judged by the
standard Hunt-Hess grading system for subarachnoid
hemorrhage.24
The phenomenology of the various types of myocardial
cell death was articulated most clearly by Baroldi,25 who
pointed out that there were 3 main patterns of myocardial
necrosis: (1) coagulation necrosis, the fundamental lesion of
infarction, in which the cell loses its capacity to contract and
dies in an atonic state with no myofibrillar damage; (2)
colliquative myocytolysis, in which edematous vacuolization
with dissolution of myofibrils without hypercontraction occurs in the low-output syndromes; and (3) coagulative myo-

Downloaded from http://circ.ahajournals.org/ by guest on September 1, 2014

80

Circulation

July 3, 2007

Figure 1. The neurocardiac lesion: Gross specimen of a patient


who died during an acute psychological stress shows fresh
endocardial hemorrhages (1 of many is shown by the arrow).

Figure 3. Intense mineralization within minutes of the onset of


contraction band necrosis.

cytolysis, in which the cell dies in a hypercontracted state


with early myofibrillar damage and anomalous irregular
cross-band formations.
Coagulative myocytolysis is seen in reperfused areas
around regions of coagulation necrosis in transplanted hearts,
in stone hearts, in sudden unexpected and accidental death,
and in hearts exposed to toxic levels of catecholamines, such
as in patients with pheochromocytoma. This is probably the
major lesion described by Selye as ESCN and is likely to be
the major lesion seen in animals and people who suffer acute
neurological or psychiatric catastrophes. Although coagulative myocytolysis is probably the preferred term, the terms
myofibrillar degeneration and contraction band necrosis are
commonly used in the literature. This lesion tends to calcify
early and to have a multifocal subendocardial predisposition
(Figure 1, 2, and 3).
Intense rapid calcification makes it likely that the subcellular mechanisms that underlie the development of coagulative myocytolysis involve calcium entry. Zimmerman and
Hulsmann26 reported that the perfusion of rat hearts with
calcium-free media for short periods of time creates a
situation such that on readmission of calcium there is a

massive contracture followed by necrosis and enzyme release. This phenomenon, known as the calcium paradox, can
be imitated almost exactly with reoxygenation after hypoxemia. The latter, called the oxygen paradox, has been linked
to the calcium paradox by pathological calcium entry.27 This
major ionic shift is probably the cause of the dramatic ECG
changes seen in the context of neurological catastrophe, a fact
that could explain the phenomenon of sudden unexpected
death (SUD) in many contexts.
Although SUD is now recognized as a medical problem of
major epidemiological importance, it has generally been
assumed that neurological disease rarely results in SUD. In
fact, it has been traditionally held that neurological illnesses
almost never cause sudden demise, with the occasional
patient who dies during an epileptic convulsion or rapidly in
the context of a subarachnoid hemorrhage as the exception.
Further, it has been assumed that the various SUD syndromes
(eg, sudden death in middle-aged men, sudden infant death
syndrome, sudden unexpected nocturnal death syndrome,
frightened to death (voodoo death), sudden death during an
epileptic seizure, sudden death during natural catastrophe,
sudden death associated with recreational drug abuse, sudden
death in wild and domestic animals, sudden death during
asthma attacks, sudden death during the alcohol withdrawal
syndrome, sudden death during grief after a major loss,
sudden death during panic attacks, sudden death from mental
stress, and sudden death during war) are entirely separate and
have no unifying mechanism. For example, it is generally
accepted that sudden death in middle-aged men is usually
caused by a cardiac arrhythmia (ie, ventricular fibrillation),
which results in functional cardiac arrest, whereas most work
on sudden infant death syndrome focuses on immaturity of
the respiratory control systems in the brain stem.
However, the connection between the nervous system and
the cardiopulmonary system provides the unifying link that
allows a coherent explanation for most, if not all, of the forms
of neurocardiac damage. Powerful evidence from multiple
disparate disciplines allows for a neurological explanation for
many forms of SUD.28

Figure 2. Cardiac contraction band necrosis (also known as


coagulative myocytolysis, myofibrillar degeneration). The arrow
shows 2 of the contraction bands.

Downloaded from http://circ.ahajournals.org/ by guest on September 1, 2014

Samuels

Neurogenic Heart Disease


Definition of Neurogenic
Electrocardiographic Changes
A wide variety of changes in the ECG is seen in the context
of neurological disease. Two major categories of change are
regularly noted: arrhythmias and repolarization changes. It is
likely that the increased tendency for life-threatening arrhythmias found in patients with acute neurological disease is a
result of the repolarization change, which increases the
vulnerable period during which an extrasystole would be
likely to result in ventricular tachycardia and/or ventricular
fibrillation. Thus, the essential and potentially most lethal
features of the ECG, which are known to change in the
context of neurological disease, are the ST segment and T
wave, which reflect abnormalities in repolarization. Most
often, the changes are seen best in the anterolateral or
inferolateral leads. If the ECG is read by pattern recognition
by someone who is not aware of the clinical history, it will
often be said to represent subendocardial infarction or anterolateral ischemia. The electrocardiographic abnormalities usually improve, often dramatically, with death by brain criteria.
In fact, any circumstance that disconnects the brain from the
heart (eg, cardiac transplantation, severe autonomic neuropathies caused by amyloidosis or diabetes, stellate ganglionectomy for treatment of the long QT syndrome) blunts neurocardiac damage of any cause.
The phenomenon is not rare. In a series of 100 consecutive
stroke patients, 90% showed abnormalities on the ECG
compared with 50% of a control population of 100 patients
admitted for carcinoma of the colon.29 This of course does not
mean that 90% of stroke patients have neurogenic ECG
changes. Obviously, stroke and coronary artery disease have
common risk factors, so that many ECG abnormalities in
stroke patients represent concomitant atherosclerotic coronary disease. Nonetheless, a significant number of stroke
patients have authentic neurogenic ECG changes.

Mechanism of the Production of Neurogenic


Heart Disease
Catecholamine Infusion
Josu30 first demonstrated that epinephrine infusions could
cause cardiac hypertrophy. This observation has been reproduced on many occasions, which documents the fact that
systemically administered catecholamines are not only associated with ECG changes reminiscent of widespread ischemia
but with a characteristic pathological picture in the cardiac
muscle that is distinct from myocardial infarction. An identical picture may be found in human beings with chronically
elevated catecholamines, as seen with pheochromocytoma.
Patients with stroke often have elevated systemic catecholamine levels, a fact that may in part account for the high
incidence of cardiac arrhythmias and ECG changes seen in
these patients. On light microscopy, these changes range from
increased eosinophilic staining with preservation of crossstriations to total transformation of the myocardial cell
cytoplasm into dense eosinophilic transverse bands with
intervening granularity. In severely injured areas, infiltration

The BrainHeart Connection

81

of the necrotic debris by mononuclear cells is often noted,


sometimes with hemorrhage.
Ultrastructurally, the changes in cardiac muscle are even
more widespread than they appear to be in light microscopy.
Nearly every muscle cell shows some pathological alteration,
which range from a granular appearance of the myofibrils to
profound disruption of the cell architecture with relative
preservation of ribosomes and mitochondria. Intracardiac
nerves can be seen and identified by their external lamina,
microtubules, neurofibrils, and the presence of intracytoplasmic vesicles. These nerves can sometimes be seen immediately adjacent to an area of myocardial cell damage. The
pathological changes in the cardiac muscle are usually less at
a distance from the nerve, often with a complete return to
normalcy by a distance of 2 to 4 m away from the nerve
ending.21
Myofibrillar degeneration (also known as coagulative
myocytolysis and contraction band necrosis) is an easily
recognizable form of cardiac injury, distinct in several major
respects from coagulation necrosis, which is the major lesion
of myocardial infarction.25,31 In coagulation necrosis, the cells
die in a relaxed state without prominent contraction bands.
This is not visible by any method for many hours or even
days. Calcification only occurs late, and the lesion elicits a
polymorphonuclear cell response. In stark contrast, in myofibrillar degeneration the cells die in a hypercontracted state
with prominent contraction bands (Figures 2 and 3). The
lesion is visible early, perhaps within minutes of its onset. It
elicits a mononuclear cell response and may calcify almost
immediately.31,32

Stress Plus or Minus Steroids


A similar, if not identical, cardiac lesion can be produced
with various models of stress. This concept was applied to the
heart when Selye published his monograph The Chemical
Prevention of Cardiac Necrosis in 1958.9 He found that
cardiac lesions probably identical to those described above
could be produced regularly in animals that were pretreated
with certain steroids, particularly 2- -methyl-9- fluorohydrocortisone (fluorocortisol) and then subjected to
various types of stress. Other hormones, such as dihydrotachysterol (calciferol) and thyroxine, could also sensitize animals
for stress-induced myocardial lesions, though less potently
than fluorocortisol. This so-called stress could be of multiple
types such as restraint, surgery, bacteremia, vagotomy, and
toxins. He believed that the first mediator in the translation of
these widely disparate stimuli into a stereotyped cardiac
lesion was the hypothalamus and that it, by its control over
the autonomic nervous system, caused the release of certain
agents that were toxic to the myocardial cell. Since Selyes
original work, similar experiments have been repeated in
many different types of laboratory animals with comparable
results. Although the administration of exogenous steroids
facilitates the production of cardiac lesions, it is clear that
stress alone can result in the production of morphologically
identical lesions.
Whether a similar pathophysiology could ever be repeated
in human beings is, of course, of great interest. Many
investigators have speculated on the role of stress in the

Downloaded from http://circ.ahajournals.org/ by guest on September 1, 2014

82

Circulation

July 3, 2007

pathogenesis of human cardiovascular disease and, in particular, on its relationship to the phenomenon of SUD. A few
autopsies on patients who experienced sudden death have
shown myofibrillar degeneration. Cebelin and Hirsch33 reported on a careful retrospective analysis of the hearts of 15
victims of physical assault who died as a direct result of the
assault, but without sustaining internal injuries. Eleven of the
15 individuals showed myofibrillar degeneration. Age- and
cardiac diseasematched controls showed little or no evidence of this change. This appears to represent human stress
cardiomyopathy. Whether such assaults can be considered
murder has become an interesting legal correlate of the
problem.
Because the myofibrillar degeneration is predominantly
subendocardial, it may involve the cardiac conducting system, which thus predisposes to cardiac arrhythmias. This
lesion, combined with the propensity of catecholamines to
produce arrhythmias even in a normal heart, may well raise
the risk of a serious arrhythmia. This may be the major
immediate mechanism of sudden death in many neurological
circumstances, such as subarachnoid hemorrhage, stroke,
epilepsy, head trauma, psychological stress, and increased
intracranial pressure. Even the arrhythmogenic nature of
digitalis may be largely mediated by the central nervous
system. Further evidence for this is the antiarrhythmic effect
of sympathetic denervation of the heart for cardiac arrhythmias of many types.
Furthermore, it is known that stress-induced myocardial
lesions may be prevented by sympathetic blockade with many
different classes of antiadrenergic agents, most notably,
ganglionic blockers such as mecamylamine and catecholamine-depleting agents such as reserpine.10 This suggests that
catecholamines, which are either released directly into the
heart by sympathetic nerve terminals or reach the heart
through the bloodstream after release from the adrenal medulla, may be excitotoxic to myocardial cells.
Some people who are subjected to an extreme stress may
develop an acute cardiomyopathy that presents with chest
pain and/or symptoms of heart failure. This process is most
commonly seen in older women, whose echocardiograms and
ventriculograms show a typical pattern of left ventricular
apical ballooning, which was named takotsubo-like cardiomyopathy34 because of the similarity in the appearance the
left ventricle to the Japanese octopus trapping pot, the
takotsubo. If a lethal arrhythmia does not intervene, the
process is potentially completely reversible. Some debate
exists regarding whether this syndrome (variously described
as myocardial stunning or myocardial hibernation) could be
explained by ischemia, but it is striking that this pattern of
dysfunction is most consistent with a neural rather than a
vascular distribution.35,36 Wittstein and colleagues37 reported
a series of such patients and referred to the problem as
myocardial stunning. In patients in whom endocardial biopsies were performed, contraction band lesions were found.
The finding of contraction bands suggests either catecholamine effect and/or reperfusion. The 2 mechanisms are not
mutually exclusive in that a neural stimulus could produce
both catecholamine release and coronary vasospasm followed
by vasodilation. There is no direct evidence that the nervous

system can cause coronary vasospasm, but the possibility


remains. Regardless of the precise mechanism, the fact
remains that takotsubo-like cardiomyopathy occurs after an
acute psychological stress and thereby represents an example
of a neurocardiac lesion. It seems likely that this dramatic
condition may be the tip of an iceberg under which lurks a
much larger, albeit less easily demonstrable, problem; namely
neurocardiac lesions that are not sufficiently severe and
widespread to produce gross heart failure but may predispose
to serious cardiac arrhythmias.

Nervous System Stimulation


Nervous system stimulation produces cardiac lesions that are
histologically indistinguishable from those described for
stress and catecholamine-induced cardiac damage. It has been
known for a long time that stimulation of the hypothalamus
can lead to autonomic cardiovascular disturbances,38 and
many years ago lesions in the heart and gastrointestinal tract
have been produced with hypothalamic stimulation.39,40 It has
been clearly demonstrated that stimulation of the lateral
hypothalamus produces hypertension and/or electrocardiographic changes reminiscent of those seen in patients with
central nervous system damage of various types. Furthermore, this effect on the blood pressure and ECG can be
completely prevented by C2 spinal section and stellate
ganglionectomy, but not by vagotomy, which suggests that
the mechanism of the electrocardiographic changes is sympathetic rather than parasympathetic or humoral. Stimulation
of the anterior hypothalamus produces bradycardia, an effect
that can be blocked by vagotomy. Unilateral hypothalamic
stimulation does not result in histological evidence of myocardial damage by light microscopy, but bilateral prolonged
stimulation regularly produces myofibrillar degeneration indistinguishable from that produced by catecholamine injections and stress, as previously described.41
Other methods to produce cardiac lesions of this type
include stimulation of the limbic cortex, the mesencephalic
reticular formation, the stellate ganglion, and regions known
to elicit cardiac reflexes such as the aortic arch. Experimental
intracerebral and subarachnoid hemorrhages can also result in
cardiac contraction band lesions. These neurogenic cardiac
lesions will occur even in an adrenalectomized animal,
although they will be somewhat less pronounced.20 This
evidence argues strongly against an exclusively humoral
mechanism in the intact organism. High levels of circulating
catecholamines exaggerate the electrocardiographic findings
and myocardial lesions, but high circulating catecholamine
levels are not required for the production of pathological
changes. These electrocardiographic abnormalities and cardiac lesions are stereotyped and identical to those found in the
stress and catecholamine models already outlined. They are
not affected by vagotomy and are blocked by maneuvers that
interfere with the action of the sympathetic limb of the
autonomic nervous system, such as C2 spinal section, stellate
ganglion blockade, and administration of antiadrenergic
drugs such as propranolol.
The histological changes in the myocardium range from
normal muscle on light microscopy to severely necrotic (but
not ischemic) lesions with secondary mononuclear cell infil-

Downloaded from http://circ.ahajournals.org/ by guest on September 1, 2014

Samuels

The BrainHeart Connection

83

tration. The findings on ultrastructural examination are invariably more widespread, often involving nearly every
muscle cell, even when the light microscopic appearance is
unimpressive. The electrocardiographic findings undoubtedly
reflect the total amount of muscle membrane affected by the
pathophysiological process. Thus, the ECG may be normal
when the lesion is early and demonstrable only by electron
microscopy. Conversely, the ECG may be grossly abnormal
when only minimal findings are present by light microscopy,
since the cardiac membrane abnormality responsible for the
electrocardiographic changes may be reversible. Cardiac
arrhythmias of many types may also be elicited by nervous
system stimulation along the outflow of the sympathetic
nervous system.
Figure 4. Cascade of events that lead to neurocardiac damage.

Reperfusion
The fourth and last model for the production of myofibrillar
degeneration is reperfusion, as is commonly seen in patients
who die after a period of time on a left ventricular assist pump
or after they undergo extracorporeal circulation. Similar
lesions are seen in hearts that were reperfused with angioplasty or fibrinolytic therapy. The mechanism by which
reperfusion of ischemic cardiac muscle produces coagulative
myocytolysis (also known as myofibrillar degeneration and
contraction band necrosis) involves entry of calcium after a
period of relative deprivation.41
Sudden calcium influx by one of several possible mechanisms (eg, a period of calcium deficiency with loss of
intracellular calcium, a period of anoxia followed by reoxygenation of the electron transport system, a period of ischemia followed by reperfusion, or opening of the receptoroperated calcium channels by excessive amounts of locally
released norepinephrine) may be the final common pathway
by which the irreversible contractures occur, which leads to
myofibrillar degeneration. Thus reperfusion-induced myocardial cell death may be a form of apoptosis (programmed cell
death) analogous to that seen in the central nervous system, in
which excitotoxicity with glutamate results in a similar, if not
identical, series of events.42
The precise cellular mechanism for the electrocardiographic change and the histological lesion may well reflect
the effects of large volumes of norepinephrine released into
the myocardium from sympathetic nerve terminals.43 The fact
that the cardiac necrosis is greatest near the nerve terminals in
the endocardium and is progressively less severe as one
samples muscle cells near the epicardium provides further
evidence that catecholamine toxicity produces the lesion.19
This locally released norepinephrine is known to stimulate
synthesis of adenosine 3,5-cyclic phosphate, which in turn
results in the opening of the calcium channel with influx of
calcium and efflux of potassium. This efflux of potassium
could explain the peaked T waves (a hyperkalemic pattern)
often seen early in the evolution of neurogenic electrocardiographic changes.21 The actin and myosin filaments interact
under the influence of calcium but do not relax unless the
calcium channel closes. Continuously high levels of norepinephrine in the region may result in failure of the calcium
channel to close, which leads to cell death, and finally to
leakage of enzymes out of the myocardial cell. Free radicals

released as a result of reperfusion after ischemia or by the


metabolism of catecholamines to the known toxic metabolite,
adrenochrome, may contribute to cell membrane destruction,
which leads to leakage of cardiac enzymes into the blood.44,45
Thus, the cardiac toxicity of locally released norepinephrine
falls on a continuum that ranges from a brief reversible burst
of electrocardiographic abnormalities to a pattern that resembles hyperkalemia and then finally to an irreversible failure of
the muscle cell with permanent repolarization abnormalities,
or even the occurrence of transmural cardiac necrosis with
enzyme (eg, troponin, creatine kinase) release and Q waves
seen on the ECG.
Histological changes would also represent a continuum
that ranges from complete reversibility in a normal heart
through mild changes seen only by electron microscopy to
severe myocardial cell necrosis with mononuclear cell infiltration and even hemorrhages. The amount of cardiac enzymes released and the electrocardiographic changes would
roughly correlate with the severity and extent of the pathological process. This explanation, summarized in Figure 4,
rationalizes all the observations in the catecholamine infusion, stress plus or minus steroid, nervous system stimulation,
and reperfusion models.

Concluding Remarks and Potential Treatments


In conclusion, there is powerful evidence to suggest that
overactivity of the sympathetic limb of the autonomic nervous system is the common phenomenon that links the major
cardiac pathologies seen in neurological catastrophes. These
profound effects on the heart may contribute in a major way
to the mortality rates of many primarily neurological conditions such as subarachnoid hemorrhage, cerebral infarction,
status epilepticus, and head trauma. These phenomena may
also be important in the pathogenesis of SUD in adults,
sudden infant death, sudden death during asthma attacks,
cocaine- and amphetamine-related deaths, and sudden death
during the alcohol withdrawal syndrome, all of which may be
linked by stress and catecholamine toxicity.
Investigations aimed at alteration of the natural history of
these events with catecholamine receptor blockade, calciumchannel blockers, free-radical scavengers, and antioxidants

Downloaded from http://circ.ahajournals.org/ by guest on September 1, 2014

84

Circulation

July 3, 2007

Figure 5. Possible therapeutic approaches aimed to prevent neurocardiac damage. GABA indicates gamma aminobutyric acid.

are in progress in many centers around the world and are


summarized in Figure 5.

Disclosures
None.

References
1. Cannon WB. Voodoo death. Am Anthropologist. 1942;44(new series):
169 118.
2. Engel G. Sudden and rapid death during psychological stress. Ann Intern
Med. 1971;74:771782.
3. Richter CP. On the phenomenon of sudden death in animal and man.
Psychosomatic Med. 1957;19:191198.
4. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular
effects of human insular cortex stimulation. Neurology. 1992;42:
17271732.
5. Byer E, Ashman R, Toth LA. Electrocardiogram with large upright T
wave and long Q-T intervals. Am Heart J. 1947;33:796 801.
6. Levine HD. Non-specificity of the electrocardiogram associated with
coronary heart disease. Am J Med. 1953;15:344 350.
7. Burch GE, Myers R, Abildskov JA. A new electrocardiographic pattern
observed in cerebrovascular accidents. Circulation. 1954;9:719 726.
8. Cropp CF, Manning GW. Electrocardiographic change simulating myocardial ischaemia and infarction associated with spontaneous intracranial
haemorrhage. Circulation. 1960;22:2538.
9. Selye H. The Chemical Prevention of Cardiac Necrosis. New York, NY:
Ronald Press; 1958.
10. Raab W, Stark E, MacMillan WH, Gigee WR. Sympathogenic origin and
anti-adrenergic prevention of stress-induced myocardial lesions.
Am J Cardiol. 1961;8:203211.
11. Barger AC, Herd JA, Liebowitz MR. Chronic catheterization of coronary
artery induction of ECG pattern of myocardial ischemia by intracoronary
epinephrine. Proc Soc Exp Biol Med. 1961;107:474 477.
12. Melville KI, Blum B, Shister HE, Silver MD. Cardiac ischemic changes
and arrhythmias induced by hypothalamic stimulation. Am J Cardiol.
1963;12:781791.
13. Oppenheimer SM, Cechetto DF. Cardiac chronotropic organization of the
rat insular cortex. Brain Res. 1990;533:66 72.
14. Cechetto DF, Saper CB. Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat. J Comp Neurology.
1987;262:27 45.
15. Cheung RTF, Hachinski V. The insula and cerebrogenic sudden death.
Arch Neurol. 2000;57:16851688.
16. Cheshire WP, Saper CB. The insular cortex and cardiac response to
stroke. Neurology. 2006;66:1296 1297.
17. Koskelo P, Punsar SO, Sipila W. Subendocardial haemorrhage and ECG
changes in intracranial bleeding. BMJ. 1964;1:1479 1483.
18. Connor RCR. Myocardial damage secondary to brain lesions. Am Heart J.
1969;78:145148.
19. Greenshoot JH, Reichenbach DD. Cardiac injury and subarachnoid haemorrhage. J Neurosurg. 1969;30:521531.

20. Hawkins WE, Clower BR. Myocardial damage after head trauma and
simulated intracranial haemorrhage in mice: the role of the autonomic
nervous system. Cardiovasc Res. 1971;5:524 529.
21. Jacob WA, Van Bogaert A, DeGroot-Lasseel MHA. Myocardial ultrastructural and haemodynamic reactions during experimental subarachnoid
haemorrhage. J Moll Cell Cardiol. 1972;4:287298.
22. McNair JL, Clower BR, Sanford RA. The effect of reserpine pretreatment
on myocardial damage associated with simulated intracranial haemorrhage in mice. Eur J Pharmacol. 1970;9:1 6.
23. Hunt D, Gore I. Myocardial lesions following experimental intracranial
hemorrhage: prevention with propranolol. Am Heart J. 1972;83:232236.
24. Tung P, Kopelnik A, Banki N, Ong K, Ko N, Lawton MT, Gress D, Drew
B, Foster E, Parmley W, Zaroff J. Predictors of neurocardiogenic injury
after subarachnoid hemorrhage. Stroke. 2004;35:548 553.
25. Baroldi F. Different morphological types of myocardial cell death in man. In:
Fleckstein A, Rona G, eds. Recent Advances in Studies in Cardiac Structure
and Metabolism. Pathophysiology and Morphology of Myocardial Cell
Alteration. Vol 6. Baltimore, Md: University Park Press, 1975.
26. Zimmerman ANA, Hulsmann WC. Paradoxical influence of calcium ions
on their permeability of the cell membranes of the isolated rat heart.
Nature. 1966;211:616 647.
27. Hearse DJ, Humphrey SM, Bullock GR. The oxygen paradox and the
calcium paradox: two facets of the same problem? J Moll Cell Cardiol.
1978;10:641 668.
28. Samuels MA. Neurally induced cardiac damage. Neurol Clin. 1993;11:
273292.
29. Dimant J, Grob D. Electrocardiographic changes and myocardial damage
in patients with acute cerebrovascular accidents. Stroke. 1977;8:
448 455.
30. Josu O. Hypertrophie cardiaque cause par ladrenaline and la toxine
typhique. C R Soc Biol (Paris). 1907;63:285287.
31. Karch SB, Billingham ME. Myocardial contraction bands revisited. Hum
Pathol. 1986;17:9 13.
32. Rona G. Catecholamine cardiotoxicity. J Moll Cell Cardiol. 1985;17:
291306.
33. Cebelin M, Hirsch CS. Human stress cardiomyopathy. Hum Pathol.
1980;11:123132.
34. Sato H, Tateishi H, Uchida T. Takotsubo-type left ventricular dysfunction
due to multivessel coronary spasm. In: Kodama K, Haze K, Hori M, eds.
Clinical Aspects of Myocardial Injury: From Ischemia to Heart Failure.
Tokyo, Japan: Kagakuhyoronsha Publishing Co; 1990:56 64.
35. Angelakos ET. Regional distribution of catecholamines in the dog heart.
Circ Res. 1965;16:39 44.
36. Murphree SS, Saffitz JE. Quantitative autoradiographic delineation of the
distribution of beta-adrenergic receptors in canine and feline left ventricular myocardium. Circ Res. 1987;60:568 579.
37. Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, Schulman SP,
Gerstenblith G, Wu KC, Rade JJ, Bivalaqua TJ, Champion HC. Neurohumoral features of myocardial stunning due to sudden emotional stress.
N Engl J Med. 2005;352:539 548.
38. Dikshit BB. The production of cardiac irregularities by excitation of the
hypothalamic centres. J Physiol. 1934;81:382394.
39. Karplus JP, Kreidl A. Gehirn und Sympathicus. Sympathicusleitung im
Gehirn und Halsmark [German]. Pflugers Arch. 1912;143:109 127.
40. Karplus JP, Kreidl A. Gehirn und Sympathicus. Uber Beziehungen der
Hypothalamaszentren zu Blutdruck und innerer Sekretion [German].
Pflugers Arch. 1927;215:667 674.
41. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged
sword? J Clin Invest. 1985;76:1319.
42. Gottlieb R, Burleson KO, Kloner RA Babior BM, Engler RL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest.
1994;94:16211628.
43. Eliot RS, Todd GL, Pieper GM, Clayton FC. Pathophysiology of catecholamine-mediated myocardial damage. J S C Med Assoc. 1979;75:
513518.
44. Singal PK, Kapur N, Dhillon KS, Beamish RE, Dhalla NS. Role of free
radicals in catecholamine-induced cardiomyopathy. Can J Physiol
Pharmacol. 1982;60:1390 1397.
45. Meerson FZ. Pathogenesis and prophylaxis of cardiac lesions in stress.
Adv Myocardiol. 1983;4:321.
KEY WORDS: antioxidants apoptosis cardiomyopathy cerebral
infarction death, sudden nervous system, autonomic nervous system,
sympathetic

Downloaded from http://circ.ahajournals.org/ by guest on September 1, 2014